Temozolomide is an oral alkylating agent that has been in use since the turn of the century for the treatment of aggressive brain tumors.
Temozolomide is thought to alkylate/methylate deoxyribonucleic acid (DNA) at the N-7 and O-6 positions of guanine (Newlands E S et al., Cancer Treatment Reviews 23:35-61, 1997). This methylation is believed to act as a trigger for apoptosis, which ultimately results in lesions in the DNA and death of the cancer cells. In some tumor cells, the effectiveness of temozolomide is limited by the presence of O-6-methylguanine-DNA methyltransferase (MGMT) or O-6-alkylguanine-DNA alkyltransferase (AGT or AGAT) in the cells. These enzymes are part of the cell-repair machinery of a cell and can reverse the methylation caused by temozolomide.
Since tumor cells that synthesize the MGMT/AGT enzyme are more resistant to killing by temozolomide, various researchers have investigated whether the inclusion of O-6-benylguanine (O6-BG), an inhibitor of MGMT, would be able to overcome this resistance and improve the drug's therapeutic effectiveness. In the laboratory, this combination indeed showed increased activity in tumor cell culture in vitro and in animal models in vivo (Ueno et al., Mol. Cancer Ther. 5(3):732-8, 2006). However, a recently completed phase II clinical trial with brain tumor patients yielded mixed outcomes; while there was some improved therapeutic activity when 06-BG and temozolomide were given to patients with temozolomide-resistant anaplastic glioma, there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant glioblastoma multiforme (Quinn et al., J. Clin. Oncol., 27(8):1262-1267, 2009). As such, the effectiveness of temozolomide in the treatment of cancers could be improved.